Infection with Schistosoma mansoni remains a major public health problem in much of Africa, and it is now clear that chronic schistosome infections can lead to both severe and subtle morbidity. The latter is under- estimated, but likely has the greater impact on overall global public health. We and others have evidence that resistance to reinfection with schistosomes can develop after praziquantel treatment, especially when this involves multiple rounds of treatments and reinfections. Understanding the immune responses that cause severe and subtle morbidity and are responsible for resistance to reinfection and the immunoregulation of those responses may be important in determining effective scheduling of mass chemotherapy as well as moving beyond mass chemotherapy as the only means of control. While schistosomiasis is a public health threat, it can also impact unrelated immune responses; for example, to current vaccines and in situations like clinical trials of new candidate vaccines, co-infections, atopic allergies and autoimmune diseases. The objectives of this proposal are to: a) achieve a better understanding of the underlying immunoregulation and immune responses that correlate with both morbidity and resistance to reinfection; and b) determine the impact of schistosomiasis on standard Expanded Program of Immunization vaccine responses in infants born of mothers with schistosomiasis and adults immunized before or after treatment for their schistosomiasis. The Specific Aims are: 1) Functional analyses of T regulatory and Th17 cells in schistosomiasis; 2) Analyses of the development of altered immune responses and morbidity in children following standard annual mass drug administration with praziquantel for control of schistosomiasis; and 3) Establishment and mechanisms of the impact of schistosomiasis on non-schistosome related vaccine-induced immune responses in children born of infected mothers, and in adults. Each Specific Aim is based on hypotheses generated from preliminary findings and the literature on human immunology in schistosomiasis. The research will be done with cohorts in and near Kisumu, Kenya, where there is year-round transmission of S. mansoni in Lake Victoria, and is based on 14 years of collaborative, longitudinal studies. The methodologies will primarily be analyses of the relationships between well defined clinical and epidemiologic findings and such immune parameters as: peripheral blood leukocyte phenotyping by flow cytometry; responses to schistosome and other antigens by whole blood cultures followed by multiplex analyses of the cytokines produced, and plasma antibody levels. These studies will produce practical, public health-related findings, such as the time needed after helminth treatment before immunizations, and possible optimization of mass drug administration control programs to achieve reductions in infection-associated morbidity. They will also answer basic immunologic questions about immunoregulation during schistosomiasis and how schistosome infections alter adaptive immune responses. PUBLIC HEALTH RELEVANCE: Schistosomiasis is a debilitating, chronic worm infection of about 200 million people in much of Africa and parts of Asia, the Middle East and South America that impacts childhood development, can lead to life threatening disease, and can interfere with the ability to respond to vaccines against other infections, but there is only one effective drug and no vaccine for this widespread disease. These immunologic studies will determine if and how people become more resistant to reinfection due to multiple treatments with the drug praziquantel as well as see if schistosomiasis hampers the ability of infants and adults to respond well to standard vaccines and how this interference is mediated. These studies are relevant to both current recommended treatment programs and future interventions to control the global public health challenge of schistosomiasis and other diseases in which efficacy of standard childhood or adult vaccines may be damped due to schistosomiasis.